Nora D. Volkow, M.D. Director

National Institute on Drug Abuse

For Opiate Addiction • Methadone • Naltrexone • Buprenorphine • Buprenorphine/Naloxone

Medications Currently Available

For Nicotine Addiction • Nicotine Replacement Therapies (NRT) • Bupropion • Varenicline

For Alcoholism • Disulfiram • Naltrexone • Acamprosate • Naltrexone Depot • Topiramate

Therapies for Smoking Cessation

• 7 FDA approved pharmaco-therapies:

- 5 NRT and 2 non-NRT

• Cessation treatment has limited efficacy after 6 months

Only 20% using pharmacotherapy are abstinent for more than a year.

Treatment Abstinence Rate at 6 mo, %

Self-help and Quitline 8.5% and 12.7%

Counseling alone 14.6%

* Varenicline (2mg/day and 1 mg/day) 33.2% and 25.4%

* Bupropion SR 24.2%

* Nicotine patch 23.4%

Medication and counseling 27.6%

* Treating Tobacco Dependence in Light of the 2008 US Department of Health and Human Services Clinical Practice Guideline

Varenicline & Bupropion SR Combination Therapy for Smoking Cessation

Ebbert JO et al., Nic Tobacco Research 2009;11(3):234-239.

0

10

20

30

40

50

60

70

80

Varenicline +

Bupropion

Varenicline Bupropion

3 months

6 months

7-d

ay

po

int-

pre

vale

nce

smo

kin

g a

bst

inen

ce r

ate

s

71%

58%

50%

33% 36%

25%

reported smoking

Gonzales et al., 2006;Jorenby et al., 2006

Full and Partial Agonists vs Antagonists Treatment Strategies for Opioid Addiction

effect

no effect

agonist antagonist

an agonist drug has an active site of similar shape to the endogenous ligand so binds to the receptor

and produces the same effect

an antagonist drug is close enough in shape to bind to the receptor but not close enough to produce an effect. It also

takes up receptor space and so prevents the endogenous

ligand from binding O

pio

id E

ffec

t

Full Agonist (Methadone)

Partial Agonist (Buprenorphine)

Antagonist (Naloxone)

Log Dose

Normal Control

Methadone Maintained Patient

Source: Kling et al., JPET, 2000.

Specific Binding

[18F]cyclofoxy (m ligand)

30-35 % receptor occupancy for

methadone doses > 80 mg a day

Specific Binding

[11C]carfentail (m ligand)

27-47 % occupancy for 2mg Bup

85-92% occupancy for 16 mg Bup

94-98% occupancy for 32 mg Bup

Greenwald, MK et al., Neuropsychoph, 2003.

C = Counseling Only C+M = Counseling & Methadone Started in Prison

11%

85% 80%

C

64%

46%

C + M

% of 180 days post-release on treatment

% of 180 days post-release used heroin

Gordon, MS et al., Addiction 103:1333-1342, 2008.

Treatment Linkage & Days Used Heroin

6 Months Post-release

70%

60%

50%

40%

30%

20%

10%

0%

90%

Per

cen

t Treatment Retention in HIV-Infected Patients Receiving Buprenorphine/Naloxone (n=303)

% Retained

% Not Retained

% Lost to

Follow-Up

Fiellin DA et al., JAIDS 2011; 56(Suppl 1) S33-S38.

IMPLANTABLE buprenorphine -- Probuphine™

Ling, W. et al. JAMA 2010;304:1576-1583

120

100

80

60

40

20

0

Nu

mb

er o

f P

ati

ents

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Week

Buprenorphine

Placebo

Retention of Patients Through the Trial

Trials required for FDA approval finished; could be available in 2013

Delivers buprenorphine for 6 months

(Titan Pharmaceuticals)

Although We Do Have Treatments That Work

We Face Some Major Challenges in Using Them

• Criminal Justice System’s

Reluctance to Use

• Many Countries’

Reluctance to Use

Krupitzky et al.,

unpublished

Placebo: N=124

XR-NTX: N=126

IM Injection

every 4 weeks

for 24 weeks

NO Medications to Treat Addictions to:

• Cocaine Addiction

• Methamphetamine Addiction

• Marijuana Addiction

Vaccines as a promising strategy

B cells produce antibodies

Cocaine bound to cholera toxin B

Antibodies enter the

bloodstream When cocaine is introduced into

the bloodstream, antibodies bind it

Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1): 60-70.

Mechanism of Action of Vaccine Against Cocaine Addiction

No vaccine: Quick absorption at the Blood-brain barrier

Vaccine-stimulated antibodies delay absorption

Targeting Brain Circuits Involved in Addiction

Hipp

MEMORY/ LEARNING

Amyg

VP REWARD

EXECUTIVE FUNCTION

MOTIVATION/ DRIVE

OFC

INHIBITORY CONTROL

D. Striatum

PFC

NAcc

ACG

Potential Targets for Medications Development

Kappa opioid receptor antagonists (JDTic)

Dopamine (D3) receptor antagonists (Buspirone)

5HT2A receptor antagonists

5HT2C receptor agonists (Lorcarserin)

mGluR5 receptor antagonists (Fenobam)

mGluR2/3 allosteric modulators

CRH1 antagonists

FAAH inhibitors

Orexin antagonists

NK-1 antagonists

Biologics (vaccines, mAbs, engineered enzymes)

Pharmaceutical Companies that have Reduced or Eliminated Psychiatry Research from their

Portfolios within the Past 3 Years

• GlaxoSmithKline

• Novartis

• Astra-Zeneca

• Sanofi-Aventis

• Cephalon

IOM Recommendations: Overcome Critical Market Barriers

Government Funding of New Drug Development

Expansion and Enhancement of Substance Abuse Treatment System

Guaranteed Market

Extended Market Exclusivity

Vaccines

• Human studies

Nicotine vaccine

Cocaine vaccine

• Preclinical studies

Heroin vaccine

Methamphetamine vaccine

Naltrexone & Buprenorphine for the TX of Cocaine

Rate

s (%

) of

Posi

tive

Uri

nes

fo

r

Co

cain

e M

eta

boli

tes

Gerra G et al., J Psychopharmacol Online First January 9, 2006.

0

5

10

15

20

25

30

35

40

45

Week 1 Week 4 Week 12

3 37

40

42

18

33

9

--Naltrexone Alone

--Naltrexone + Buprenorphine

Cubic-root transformed longest duration of cocaine abstinence

Mu

Op

ioid

Rec

epto

rs B

PN

D

Ghitza et al 2010

Mu Opioid Receptors are Increased in Cocaine Abusers

and this is Associated with more Cocaine Use during Tx

Colfax GN et al., Arch Gen Psychiatry 2011; 68:1168-1175.

Clinical Trials for Medications for METH

Elkashef et al., Neuropsychopharm 2008;

33:1162-1170.

BUPROPION MIRTAZAPINE

Percentage of Patients with METH-Free Urine Week Baseline Low Meth Use

Study week elapsed since randomization

100

90

80

70

60

50

40

30

20

10

0

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

p=0.03

GEE fitted lines Bupropion Placebo

Group means Bupropion Placebo T

esti

ng

Po

siti

ve

for

Met

ha

mp

het

am

ines

,%

Mirtazapine (n=30) Observed Fitted

Placebo (n=30) Observed Fitted

0 2 3 4 5 6 7 8 9 10 11 12 (30;30) (28;27) (25;23) (27;27) (27;22) (26;27) (26;25) (27;24) (26;24) (23;23) (23;23) (27;27)

Study Week (No. of Placebo Arm; Mirtazapine Arm Samples)

100

80

60

40

20

0

Ret

enti

on

Pro

bab

ilit

y

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Placebo

Dronabinol

0 1 2 3 4 5 6 7 8

Week

8

7

6

5

4

3

2

1

0

WD

S s

core

Placebo

Dronabinol

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Visit

Retention Rates in

Dronabinol Treated vs Placebo

Withdrawal Discomfort Score in

Dronabinol Treated vs Placebo

Levin FR et al., Drug and Alcohol Dependence 2011; 116: 142-150.

Current Status of Anti-cocaine/Anti-nicotine Vaccines in Clinical Trials

Shen XY, Orson FM and Kosten TR, Clin Pharm & Ther 2012; 91(1): 60-70.

Vaccine Target Status Characteristics Company Country

TA-CD

Cocaine

Cocaine Phase IIB Cholera toxin B

conjugate

Celtic

Pharmaceuticals

United

Kingdom

NIC002 Nicotine Phase II Virus-like vaccine Cytos Biotechnology/

Novartis

Switzerland

TA-NIC

Nicotine Phase II A recombinant cholera

toxin conjugate

Celtic

Pharmaceuticals

United

Kingdom

NicVax Nicotine Phase III A bacterial exoprotein Nabi

Biopharmaceuticals/

GlaxoSmithKline

United

States

Pharmacological Strategies to Attenuate Nicotine Reinforcement and Alleviate Withdrawal

D’Souza MS and Markou A. Addiction Science and Clinical Practice July 2011: 4-16.